Method for providing a cathartic effect

ABSTRACT

The present invention relates to a novel method for providing a cathartic effort to a patient in need of cathartic induction, which comprises administering to the patient a cathartic-inducing effective amount of halogenated bioactive lipid comprising the following patial structure (I): 
                         
The method is useful for relieving or preventing constipation, and also for cleansing the gastrointestinal tract.

CROSS REFERENCE FOR RELATED APPLICATIONS

This is a divisional of application Ser. No. 10/147,980 filed May 20,2002, now U.S. Pat. No. 6,956,056 which claims benefit of ProvisionalApplication No. 60/291,635 filed May 18, 2001; the above noted priorapplications are all hereby incorporated by reference.

TECHNICAL FIELD

The present invention relates to a novel method for providing acathartic effect. The method is useful for relieving or preventingconstipation, and also for cleansing the gastrointestinal tract.

ART RELATED

Constipation is classified into a functional constipation such as atonicconstipation, spastic constipation and rectal constipation, an organicconstipation caused by a bowel disease and a stenosis due topostoperative adhesion and the like, and a drug-induced constipation.

Cathartics conventionally used for relieving these constipatingconditions include, for example, 1) large bowel-stimulant anthraquinonecathartics, 2) small bowel-stimulant castor oil, 3) bulking catharticssuch as carboxymethyl cellulose, 4) salt cathartics such as magnesiumsulfate and 5) saccharide cathartics such as sugar alcohol. However,these cathartics work by forcible activation due to stimulating thebowel, so that they bring diarrhea like feces and induce side effectssuch as stomachache when evacuating.

Gastrointestinal cleansing by means of promoting bowel movement has beenemployed in preparation for endoscopic examination, diagnostic orsurgical procedures such as colonoscopy, barium enema X-rays andintravenous pyelography, and emergency procedures such as emergencygastrointestinal flush for poison removal.

Electrolyte cleansing method has been generally used for cleansing thebowel, which comprises inducing diarrhea by ingesting a large volume ofisotonic water containing electrolytes only. However, because of theingestion of a large volume of water, the method could not be used forpatients with nephropathy, cardiac disorder or hypertension. Recently,PEG/electrolyte cleansing composition consisting of sodium sulfate,potassium chloride, sodium chloride, sodium bicarbonate and waterbinding polyethylene glycol (PEG), which was reported by Davis et al. in1980, is most frequently used. However, this PEG/electrolyte cleansingcomposition usually requires ingestion of a large volume of solution aslarge as 2-4 liters, and it is hard to take because of its salty, oilyand slimy tastes. For these reasons, it takes a long time and givesconsiderable pains to take the required volume. Accordingly, it has beendesired to develop a drug that is easy to take and has a desirableeffect in a smaller volume.

Meanwhile, bioactive lipids, for example, arachidonic acid metabolites,platelet-activating factor, lysophosphatidic acid, lipid-solublevitamin, endotoxin and the like, are deeply involved in regulatingdifferentiation and proliferation of cells, biophylaxis and nervefunction. The bioactive lipids derived from arachidonic acid include,for example, prostaglandins and thromboxane.

Prostaglandins (hereinafter, referred to as PG(s)) are members of classof organic carboxylic acids, which are contained in tissues or organs ofhuman or other mammals, and exhibit a wide range of physiologicalactivity. PGs found in nature (primary PGs) generally have a prostanoicacid skeleton as shown in the formula (A):

On the other hand, some of synthetic analogues of primary PGs havemodified skeletons. The primary PGs are classified to PGAs, PGBs, PGCs,PGDs, PGEs, PGFs, PGGs, PGHs, PGIs and PGJs according to the structureof the five-membered ring moiety, and further classified into thefollowing three types by the number and position of the unsaturated bondat the carbon chain moiety:

Subscript 1: 13,14-unsaturated-15-OH

Subscript 2: 5,6- and 13,14-diunsaturated-15-OH

Subscript 3: 5,6-, 13,14-, and 17,18-triunsaturated-15-OH.

Further, the PGFs are classified, according to the configuration of thehydroxyl group at the 9-position, into α type (the hydroxyl group is ofan α-configuration) and β type (the hydroxyl group is of aβ-configuration).

PGs are known to have various pharmacological and biological activities.For example, PGs induce vasodilation, inflammation and plateletagglutination; stimulate uterine and intestinal tract; and also exhibitanti ulcer action. Further, PGEs or PGFs stimulate. intestinal tract andstrongly contradict the tract, but they exert only poor enteropoolingeffects. Because of side effects such as stomachache due to theintestinal tract contraction, PGEs or PGFs cannot be used as cathartics.

SUMMARY OF THE INVENTION

The present invention relates to a novel cathartic composition that isuseful for relieving or preventing constipation, and also for cleansingthe gastrointestinal tract.

The present invention also relates to a method for relieving orpreventing constipation as well as a method for cleansing thegastrointestinal tract.

The present inventor has conducted pharmacological investigations on thebioactive lipids, and found that halogenated bioactive lipid having atleast the following partial structure exerts a remarkable catharticaction, which has resulted in the completion of the present invention.

Namely, the present invention relates to a method for providing acathartic effect to a patient in need of cathartic induction, whichcomprises administering to the patient a cathartic-inducing effectiveamount of halogenated bioactive lipid comprising the following partialstructure (I):

wherein B is —CH₂—CH₂—, —CH═CH— or —C≡C—;

Z is

wherein R₄ and R₅ are hydrogen, hydroxy, halogen, lower alkyl, loweralkoxy or hydroxy(lower)alkyl, wherein R₄ and R₅ are not hydroxy andlower alkoxy at the same time;

X₁ and X₂ are hydrogen, lower alkyl or halogen, and at least one of themis halogen.

Especially the present invention relates to a method for providing acathartic effect to a patient in need of cathartic induction, whichcomprises administering to the patient a cathartic-inducing effectiveamount of halogenated bioactive lipid represented by the formula (II):

wherein L, M and N are hydrogen, hydroxy, halogen, lower alkyl,hydroxy(lower)alkyl or oxo, wherein at least one of L and M is a groupother than hydrogen, and the five-membered ring may have at least onedouble bond;

A is —CH₂OH, —COCH₂OH, —COOH or a functional derivative thereof;

B is —CH₂—CH₂—, —CH═CH— or —C≡C—;

Z is

wherein R₄ and R₅ are hydrogen, hydroxy, halogen, lower alkyl, loweralkoxy or hydroxy(lower)alkyl, wherein R₄ and R₅ are not hydroxy andlower alkoxy at the same time;

R₁ is a saturated or unsaturated bivalent lower or medium aliphatichydrocarbon residue, which is unsubstituted or substituted with halogen,alkyl, hydroxy, oxo, aryl or heterocyclic group and at least one ofcarbon atoms in the aliphatic hydrocarbon is optionally substituted byoxygen, nitrogen or sulfur;

X₁ and X₂ are hydrogen, lower alkyl or halogen, and at least one of themis halogen; and

Ra is a saturated or unsaturated lower or medium aliphatic hydrocarbonresidue, which is unsubstituted or substituted with halogen, oxo,hydroxy, lower alkoxy, lower alkanoyloxy, cyclo(lower)alkyl,cyclo(lower)alkyloxy, aryl, aryloxy, heterocyclic or hetrocyclic-oxygroup; cyclo(lower)alkyl; cyclo(lower)alkyloxy; aryl; aryloxy;heterocyclic or heterocyclic-oxy group.

In another aspect, the present invention relates to a catharticcomposition comprising a cathartic effective amount of halogenatedbioactive lipid comprising the above partial structure (I).

Especially, the present invention also relates to a catharticcomposition comprising a cathartic effective amount of halogenatedbioactive lipid represented by the above formula (II).

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 represents HPLC pattern of compound 5. The compound was resolvedinto epimers (compounds 6 and 7).

DETAILED DESCRIPTION OF THE INVENTION

The nomenclature of the PG compounds, which are one of the bioactivelipids, used herein is based on the numbering system of prostanoic acidrepresented in the above formula (A).

The formula (A) shows a basic skeleton of the C-20 carbon atoms, but thepresent invention is not limited to those having the same number ofcarbon atoms. In the formula (A), the numbering of the carbon atomswhich constitute the basic skeleton of the PG compounds starts at thecarboxylic acid (numbered 1), and carbon atoms in the α-chain arenumbered 2 to 7 towards the five-membered ring, those in the ring are 8to 12, and those in the ω-chain are 13 to 20. When the number of carbonatoms is decreased in the α-chain, the number is deleted in the orderstarting from position 2; and when the number of carbon atoms isincreased in the α-chain, compounds are named as substitution compoundshaving respective substituents at position 2 in place of the carboxygroup (C-1). Similarly, when the number of carbon atoms is decreased inthe ω-chain, the number is deleted in the order starting from position20; and when the number of carbon atoms is increased in the ω-chain, thecarbon atoms beyond position 20 are named as substituents.Stereochemistry of the compounds is the same as that of the aboveformula (A) unless otherwise specified.

In general, each of the terms PGD, PGE and PGF represents a PG compoundhaving hydroxy groups at positions 9 and/or 11, but in the presentspecification, these terms also include those having substituents otherthan the hydroxy group at positions 9 and/or 11. Such compounds arereferred to as 9-dehydroxy-9-substituted-PG compounds or11-dehydroxy-11-substituted-PG compounds. A PG compound having hydrogenin place of the hydroxy group is simply named as 9- or 11-dehydroxycompound.

As stated above, the nomenclature of the prostaglandin compounds isbased on the prostanoic acid skeleton. However, in case the compound hasa similar partial structure as a prostaglandin, the abbreviation of “PG”may be used. Thus, a PG compound of which α-chain is extended by twocarbon atoms, that is, having 9 carbon atoms in the α-chain is named as2-decarboxy-2-(2-carboxyethyl)-PG compound. Similarly, a PG compoundhaving 11 carbon atoms in the α-chain is named as2-decarboxy-2-(4-carboxybutyl)-PG compound. Further, a PG compound ofwhich ω-chain is extended by two carbon atoms, that is, having 10 carbonatoms in the ω-chain is named as 20-ethyl-PG compound. These compounds,however, may also be named according to the IUPAC nomenclatures.

The PG compound used in the present invention may include any PGderivatives or analogs insofar as having a hydroxy group at 15 positionand at least one halogen atom at 16 position. Accordingly, for example,a PG type 1 compound having a double bond at 13-14 position, a PG type 2compound having two double bond at 13-14 and 5-6 position, a PG type 3compound having three double bond at 5-6, 13-14 and 17-18 position,13,14-dihydro-PG compound wherein the double bond at 13-14 position issingle bond.

Typical examples of the compounds used in the present invention includePG type 1, PG type 2, PG type 3, 13,14-dihydro-PG type 1,13,14-dihydro-PG type 2, 13,14-dihydro-PG type 3 and the derivatives oranalogs thereof.

Examples of the analogs (including substituted derivatives) orderivatives include a PG compound of which carboxy group at the end ofα-chain is esterified; a compound of which α-chain is extended;physiologically acceptable salt thereof; a compound having a double bondat 2-3 position or a triple bond at position 5-6, a compound havingsubstituent(s) at position 3, 5, 6, 16, 17, 18, 19 and/or 20; and acompound having lower alkyl or a hydroxy (lower) alkyl group at position9 and/or 11 in place of the hydroxy group.

According to the present invention, preferred substituents at position3, 17, 18 and/or 19 include alkyl having 1-4 carbon atoms, especiallymethyl and ethyl. Preferred substituents at position 16 include loweralkyl such as methyl and ethyl, hydroxy, halogen atoms such as chlorineand fluorine, and aryloxy such as trifluoromethylphenoxy. According tothe invention, at least one of substituents at position 16 issubstituted by halogen atom. Preferred substituents at position 17include lower alkyl such as methyl and ethyl, hydroxy, halogen atomssuch as chlorine and fluorine, and aryloxy such astrifluoromethylphenoxy. Preferred substituents at position 20 includesaturated or unsaturated lower alkyl such as C1-4 alkyl, lower alkoxysuch as C1-4 alkoxy, and lower alkoxy alkyl such as C1-4 alkoxy-C1-4alkyl. Preferred substituents at position 5 include halogen atoms suchas chlorine and fluorine. Preferred substituents at position 6 includean oxo group forming a carbonyl group. Stereochemistry of PGs havinghydroxy, lower alkyl or hydroxy(lower)alkyl substituent at position 9and/or 11 may be α, β or a mixture thereof.

Further, the above derivatives and analogs may be compounds having analkoxy, cycloalkyl, cycloalkyloxy, phenoxy or phenyl group at the end ofthe ω-chain where the chain is shorter than the primary PGs.

An especially preferred compound used in the present invention isrepresented by the formula (III):

wherein L and M are hydrogen, hydroxy, halogen, lower alkyl,hydroxy(lower)alkyl or oxo, wherein at least one of L and M is a groupother than hydrogen, and the five-membered ring may have at least onedouble bond;

A is —CH₂OH, —COCH₂OH, —COOH or a functional derivative thereof;

B is —CH₂—CH₂—, —CH═CH— or —C≡C—;

Z is

wherein R₄ and R₅ are hydrogen, hydroxy, halogen, lower alkyl, loweralkoxy or hydroxy(lower)alkyl, wherein R₄ and R₅ are not hydroxy andlower alkoxy at the same time;

R₁ is a saturated or unsaturated bivalent lower or medium aliphatichydrocarbon residue, which is unsubstituted or substituted with halogen,alkyl, hydroxy, oxo, aryl or heterocyclic group, and at least one ofcarbon atoms in the aliphatic hydrocarbon is optionally substituted byoxygen, nitrogen or sulfur;

X₁ and X₂ are hydrogen, lower alkyl or halogen, and at least one of themis halogen;

R₂ is a single bond or lower alkylene; and

R₃ is lower alkyl, lower alkoxy, cyclo(lower)alkyl,cyclo(lower)alkyloxy, aryl, aryloxy, heterocyclic group orheterocyclic-oxy group.

Especially the compound of formula (II), wherein B is —CH₂—CH₂— and X₁and X₂ are same or different halogen atoms, that is, the compoundrepresented by formula (IV):

wherein L and M are hydrogen, hydroxy, halogen, lower alkyl,hydroxy(lower)alkyl or oxo, wherein at least one of L and M is a groupother than hydrogen, and the five-membered ring may have at least onedouble bond;

A is —CH₂OH, —COCH₂OH, —COOH or a functional derivative thereof;

B′ is —CH₂—CH₂—;

Z is

wherein R₄ and R₅ are hydrogen, hydroxy, halogen, lower alkyl, loweralkoxy or hydroxy(lower)alkyl, wherein R₄ and R₅ are not hydroxy andlower alkoxy at the same time;

R₁ is a saturated or unsaturated bivalent lower or medium aliphatichydrocarbon residue, which is unsubstituted or substituted with halogen,alkyl, hydroxy, oxo, aryl or heterocyclic group and at least one ofcarbon atoms in the aliphatic hydrocarbon is optionally substituted byoxygen, nitrogen or sulfur;

X₁′ and X₂′ are same or different halogen atoms;

R₂ is a single bond or lower alkylene; and

R₃ is lower alkyl, lower alkoxy, cyclo(lower)alkyl,cyclo(lower)alkyloxy, aryl, aryloxy, heterocyclic group orheterocyclic-oxy group

is novel and preferred according to the present invention, and coveredby the scope of the present invention.

In the above formula, the term “unsaturated” in the definitions for R₁and Ra is intended to include at least one or more double bonds and/ortriple bonds that are isolatedly, separately or serially present betweencarbon atoms of the main and/or side chains. According to the usualnomenclature, an unsaturated bond between two serial positions isrepresented by denoting the lower number of the two positions, and anunsaturated bond between two distal positions is represented by denotingboth of the positions.

The term “lower or medium aliphatic hydrocarbon” refers to a straight orbranched chain hydrocarbon group having 1 to 14 carbon atoms (for a sidechain, 1 to 3 carbon atoms are preferable) and preferably 1 to 10,especially 1 to 8 carbon atoms.

The term “halogen” covers fluorine, chlorine, bromine and iodine.

The term “lower” throughout the specification is intended to include agroup having 1 to 6 carbon atoms unless otherwise specified.

The term “lower alkyl” refers to a straight or branched chain saturatedhydrocarbon group containing 1 to 6 carbon atoms and includes, forexample, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl,pentyl and hexyl.

The term “lower alkylene” refers to a straight or branched chainbivalent saturated hydrocarbon group containing 1 to 6 carbon atoms andincludes, for example, methylene, ethylene, propylene, isopropylene,butylene, isobutylene, t-butylene, pentylene and hexylene.

The term “lower alkoxy” refers to a group of lower alkyl-O—, whereinlower alkyl is as defined above.

The term “hydroxy(lower)alkyl” refers to a lower alkyl as defined abovewhich is substituted with at least one hydroxy group such ashydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl and1-methyl-1-hydroxyethyl.

The term “lower alkanoyloxy” refers to a group represented by theformula RCO—O—, wherein RCO— is an acyl group formed by oxidation of alower alkyl group as defined above, such as acetyl.

The term “cyclo(lower)alkyl” refers to a cyclic group formed bycyclization of a lower alkyl group as defined above but contains threeor more carbon atoms, and includes, for example, cyclopropyl,cyclobutyl, cyclopentyl and cyclohexyl.

The term “cyclo(lower)alkyloxy” refers to the group ofcyclo(lower)alkyl-O—, wherein cyclo(lower)alkyl is as defined above.

The term “aryl” may include unsubstituted or substituted aromatichydrocarbon rings (preferably monocyclic groups), for example, phenyl,tolyl, xylyl. Examples of the substituents are halogen atom andhalo(lower)alkyl, wherein halogen atom and lower alkyl are as definedabove.

The term “aryloxy” refers to a group represented by the formula ArO—,wherein Ar is aryl as defined above.

The term “heterocyclic group” may include mono- to tri-cyclic,preferably monocyclic heterocyclic group which is 5 to 14, preferably 5to 10 membered ring having optionally substituted carbon atom and 1 to4, preferably 1 to 3 of 1 or 2 type of hetero atoms selected fromnitrogen atom, oxygen atom and sulfur atom. Examples of the heterocyclicgroup include furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl,isothiazolyl, imidazolyl, pyrazolyl, furazanyl, pyranyl, pyridyl,pyridazinyl, pyrimidyl, pyrazinyl, 2-pyrrolinyl, pyrrolidinyl,2-imidazolinyl, imidazolidinyl, 2-pyrazolinyl, pyrazolidinyl,piperidino, piperazinyl, morpholino, indolyl, benzothienyl, quinolyl,isoquinolyl, purinyl, quinazolinyl, carbazolyl, acridinyl,phenanthridinyl, benzimidazolyl, benzimidazolinyl, benzothiazolyl,phenothiazinyl. Examples of the substituent in this case includehalogen, and halogen substituted lower alkyl group, wherein halogen atomand lower alkyl group are as described above.

The term “heterocyclic-oxy group” means a group represented by theformula HcO—, wherein Hc is a heterocyclic group as described above.

The term “functional derivative” of A includes salts (preferablypharmaceutically acceptable salts), ethers, esters and amides.

Suitable “pharmaceutically acceptable salts” include conventionally usednon-toxic salts, for example a salt with an inorganic base such as analkali metal salt (such as sodium salt and potassium salt), an alkalineearth metal salt (such as calcium salt and magnesium salt), an ammoniumsalt; or a salt with an organic base, for example, an amine salt (suchas methylamine salt, dimethylamine salt, cyclohexylamine salt,benzylamine salt, piperidine salt, ethylenediamine salt, ethanolaminesalt, diethanolamine salt, triethanolamine salt,tris(hydroxymethylamino)ethane salt, monomethyl-monoethanolamine salt,procaine salt and caffeine salt), a basic amino acid salt (such asarginine salt and lysine salt), tetraalkyl ammonium salt and the like.These salts may be prepared by a conventional process, for example fromthe corresponding acid and base or by salt interchange.

Examples of the ethers include alkyl ethers, for example, lower alkylethers such as methyl ether, ethyl ether, propyl ether, isopropyl ether,butyl ether, isobutyl ether, t-butyl ether, pentyl ether and1-cyclopropyl ethyl ether; and medium or higher alkyl ethers such asoctyl ether, diethylhexyl ether, lauryl ether and cetyl ether;unsaturated ethers such as oleyl ether and linolenyl ether; loweralkenyl ethers such as vinyl ether, allyl ether; lower alkynyl etherssuch as ethynyl ether and propynyl ether; hydroxy(lower)alkyl etherssuch as hydroxyethyl ether and hydroxyisopropyl ether; lower alkoxy(lower)alkyl ethers such as methoxymethyl ether and 1-methoxyethylether; optionally substituted aryl ethers such as phenyl ether, tosylether, t-butylphenyl ether, salicyl ether, 3,4-di-methoxyphenyl etherand benzamidophenyl ether; and aryl(lower)alkyl ethers such as benzylether, trityl ether and benzhydryl ether.

Examples of the esters include aliphatic esters, for example, loweralkyl esters such as methyl ester, ethyl ester, propyl ester, isopropylester, butyl ester, isobutyl ester, t-butyl ester, pentyl ester and1-cyclopropylethyl ester; lower alkenyl esters such as vinyl ester andallyl ester; lower alkynyl esters such as ethynyl ester and propynylester; hydroxy(lower)alkyl ester such as hydroxyethyl ester; loweralkoxy (lower) alkyl esters such as methoxymethyl ester and1-methoxyethyl ester; and optionally substituted aryl esters such as,for example, phenyl ester, tolyl ester, t-butylphenyl ester, salicylester, 3,4-di-methoxyphenyl ester and benzamidophenyl ester; andaryl(lower)alkyl ester such as benzyl ester, trityl ester and benzhydrylester.

The amide of A means a group represented by the formula —CONR′R″,wherein each of R′ and R″ is hydrogen atom, lower alkyl, aryl, alkyl- oraryl-sulfonyl, lower alkenyl and lower alkynyl, and include for examplelower alkyl amides such as methylamide, ethylamide, dimethylamide anddiethylamide; arylamides such as anilide and toluidide; and alkyl- oraryl-sulfonylamides such as methylsulfonylamide, ethylsulfonyl-amide andtolylsulfonylamide.

Preferred examples of L and M include hydroxy and oxo, and especially, Mis hydroxy and L is oxo which has a 5-membered ring structure of, socalled, PGE type.

Preferred A is —COOH, its pharmaceutically acceptable salt, ester oramide thereof.

Preferred B is —CH₂—CH₂—, which provides so-called 13,14-dihydro typecompound.

Preferred X₁ and X₂, or X₁′ and X₂′ are fluorine atoms, which provide socalled 16,16-difluoro type compound.

Preferred R1 is a hydrocarbon residue containing 1-10 carbon atoms,preferably 6-10 carbon atoms, further at least one of carbon atoms inthe aliphatic hydrocarbon is optionally substituted by oxygen, nitrogenor sulfur.

Examples of R₁ may include the following groups:—CH₂—CH₂—CH₂—CH₂—CH₂—CH₂—,—CH₂—CH═CH—CH₂—CH₂—CH₂—,—CH₂—CH₂—CH₂—CH₂—CH═CH—,—CH₂—C≡C—CH₂—CH₂—CH₂—,—CH₂—CH₂—CH₂—CH₂—CH (CH₃)—CH₂—,—CH₂—CH₂—CH₂—CH₂—O—CH₂—,—CH₂—CH═CH—CH₂—O—CH₂—,—CH₂—C≡C—CH₂—O—CH₂—,—CH₂—CH₂—CH₂—CH₂—CH₂—CH₂—CH₂—,—CH₂—CH═CH—CH₂—CH₂—CH₂—CH₂—,—CH₂—CH₂—CH₂—CH₂—CH₂—CH═CH—,—CH₂—C≡C—CH₂—CH₂—CH₂—CH₂—,—CH₂—CH₂—CH₂—CH₂—CH₂—CH (CH₃)—CH₂—,—CH₂—CH₂—CH₂—CH₂—CH₂—CH₂—CH₂—CH₂—,—CH₂—CH═CH—CH₂—CH₂—CH₂—CH₂—CH₂—,—CH₂—CH₂—CH₂—CH₂—CH₂—CH₂—CH═CH—,—CH₂—C≡C—CH₂—CH₂—CH₂—CH₂—CH₂—,—CH₂—CH₂—CH₂—CH₂—CH₂—CH₂—CH (CH₃)—CH₂—.

Preferred Ra is a hydrocarbon containing 1-10 carbon atoms, morepreferably, 1-8 carbon atoms. Ra may have one or two side chains havingone carbon atom.

The configuration of the ring and the α- and/or ω chains in the aboveformula (II), (III) and (IV) may be the same as or different from thatof the primary PGs. The present invention also includes a mixture of acompound having a primary type configuration and a compound of anon-primary type configuration.

The typical example of the present compound is 13,14-dihydro-16-mono ordifluoro-PGE compound and the derivative or analogue thereof.

In the present invention, any of isomers such as the individualtautomeric isomers, the mixture thereof, or optical isomers, the mixturethereof, a racemic mixture, and other steric isomers may be used for thesame purpose.

According to the present invention, the subject to be treated by theinvention may be any mammalian subject including human beings.

According to the present invention, the cathartic-inducing effectiveamount may vary depending on the strain of animal or human, age, bodyweight, symptom of the subject to be treated, desired therapeuticeffect, administration route, term of treatment and the like. Typically,systemic administration of 0.00001-100 mg/kg per day by administering1-4 times per day or continuous administration may provide asatisfactory effect.

According to the present invention, the method may be carried out withthe composition of the present invention. The composition can be appliedsystemically or topically. Usually, the composition is administered byoral administration, intravenous injection (including infusion),subcutaneous injection, intra rectal administration, intra vaginaladministration and the like.

The cathartic composition of the present invention may be formulated asa composition for oral administration, for injection, for instillationor for external administration, tablet, sublingual, suppository andvaginal suppository.

The composition of the present invention may further containphysiologically acceptable additives. Said additives may includeconventional ingredients used with a bioactive lipid such as excipient,diluent, filler, resolvent, lubricant, adjuvant, binder, disintegrator,coating agent, cupsulating agent, ointment base, suppository base,aerozoling agent, emulsifier, dispersing agent, suspending agent,thickener, tonicity agent, buffering agent, soothing agent,preservative, antioxidant, corrigent, flavor, colorant, a functionalmaterial such as cyclodextrin and biodegradable polymer. The additivesmay be selected depending on the dosage form from those described ingeneral reference books of pharmaceutics.

The amount of the compound having the partial structure of formula (I)in the present composition may vary depending on the dosage form of thecomposition, and may generally be 0.0001-10.0 wt %, more preferably0.001-1.0 wt %.

Examples of solid compositions for oral administration include tablets,troches, sublingual tablets, capsules, pills, powders, granules and thelike. The solid composition may be prepared by mixing one or more activeingredients with at least one inactive diluent. The composition mayfurther contain additives other than the inactive diluents, for example,a lubricant, a disintegrator and a stabilizer. Tablets and pills may becoated with an enteric or gastroenteric film, if necessary. Thecomposition may be covered with two or more layers. The composition mayalso be adsorbed to a sustained release material, or microcapsulated.Additionally, the composition may be capsulated by means of an easilydegradable material such as gelatin. The solid composition may bedissolved in an appropriate solvent such as fatty acid or its mono, dior triglyceride to provide a soft capsule. Sublingual tablets may beprepared to provide a composition with fast-acting property.

Examples of liquid compositions for oral administration includeemulsions, solutions, suspensions, syrups and elixirs and the like. Saidcomposition may further contain conventionally used inactive diluents,e.g., purified water and ethyl alcohol. The composition may containadditives other than the inactive diluents such as adjuvant, e.g.,wetting agents and suspending agents, sweeteners, flavors, fragrancesand preservatives.

The composition of the present invention may be in the form of sprayingcomposition, which contains one or more active ingredients and may beprepared according to a known method.

Examples of injectable compositions of the present invention forparenteral administration include sterile aqueous or nonaqueoussolutions, suspensions and emulsions. Diluents for the aqueous solutionor suspension may include, for example, distilled water of injectiongrade, physiological saline and Ringer's solution. Non-aqueous diluentsfor solution and suspension may include, for example, propylene glycol,polyethylene glycol, vegetable oils such as olive oil, alcohols such asethanol and polysorbate. The composition may further comprise additivessuch as preservatives, wetting agents, emulsifying agents, dispersingagents and the like. They may be sterilized by filtration through, e.g.a bacteria-retaining filter, compounding with a sterilizer, or by meansof gas or radiation sterilization. The injectable composition may alsobe provided as a sterilized powder composition to be dissolved in aninjection-grade sterilized solvent before use.

Another form of the composition of the present invention is suppositoryor pessary, which may be prepared by mixing the active ingredients intoa base such as cacao butter that softens at body temperature, andnonionic surfactants having suitable softening temperatures may be usedto improve absorbability.

The term “treatment” used herein includes any means of control such asprevention, care, relief of the condition, attenuation of the conditionand arrest of progression.

The compound of the invention exhibits a remarkable enteropoolingeffect, and also remarkably accelerates intestinal transportability. Infact, because of the remarkable cathartic effect on animals and humanbeings, the composition of the present invention is effective forrelieving or preventing constipation, and also for cleansing thegastrointestinal tract.

Included in the types of constipation to be treated, although notparticularly limited, are functional constipation such as relaxingconstipation, spastic constipation and rectal constipation; organicconstipation caused by intestinal diseases and stenosis due topostoperative adhesion; and constipation induced by a drug such asopioid. Further, because of speedy recovery from diarrhea symptoms, thepresent compound is useful as a cathartic composition such as a laxativeand a drastic purgative.

In addition to relieving or preventing constipation, the presentcomposition may be used for preventing a patient with hernia orcardiovascular diseases from straining at stool, or for softening fecesof a patient with anorectal diseases. Moreover, the present compositionmay be used for cleansing the gastrointestinal tract in preparation forendoscopic examination or for diagnostic or surgical procedures such ascolonoscopy, barium enema X-rays and intravenous pyelography, andemergency procedures such as emergency gastrointestinal flush for poisonremoval and the like.

The present invention will be described in more detail with reference tothe following examples, which is not intended to limit the scope of thepresent invention.

SYNTHESIS EXAMPLE

(1) t-butyldimethylsilylation of the Compound 1

After dissolving 180 mg (0.337 mmol) of the compound 1 in anhydrous DMF0.38 mL, imidazole 100.8 mg (1.481 mmol) was added thereto. Next,t-butyldimethylsilyl chloride 111.7 mg (0.741 mmol) was added to thesolution and agitated for three hours at room temperature and then for14.5 hours at 37° C. Saturated aqueous ammonium chloride 0.5 mL wasadded to the reaction and then, the reaction mixture was extracted withethyl acetate 5 mL for three times. Organic layers were combined, washedwith saturated saline 5 mL and dried with anhydrous magnesium sulfate.After vacuum concentration, the residue was purified with silica gelcolumn. [Fuji Silysia Chemical BW-300 20 g, developer: ethylacetate/n-hexane=1/3→1/1] Yield: 145.3 mg; 66%; colorless oil

¹H-NNR spectrum (200 MHz/CDCl₃) of the compound 2

δ: 5.11-5.01 (m, 1H), 4.63-4.51 (m, 1H), 4.00-3.60 (m, 3H), 3.67 (s,3H), 3.56-3.40 (m, 1H), 2.40-2.10 (m, 1H), 2.30 (t, J=7.4Hz, 2H), 2.04(s, 3H), 2.00-1.08 (m, 29H), 0.99-0.85 (m, 12H), 0.08 (s, 6H)

(2) Hydrolysis of the Compound 2

After dissolving 145.3 mg (0.224 mmol) of the compound 2 in ethanol 6.3mL, 1N-sodium hydroxide 0.67 mL (0.67 mmol) was added thereto andagitated for three hours at room temperature. Then 1N-sodium hydroxide0.45 mL (0.45 mmol) was added to the solution and agitated for 16 hoursat room temperature. Water 1 mL was added to the solution, which wasacidified (pH4) with 1N-hydrochloric acid 0.79 mL. After that, saturatedsaline 1.5 mL was added to the solution, and then, the reaction mixturewas extracted with ethyl acetate 10 mL for three times. Organic layerswere combined and dried with anhydrous magnesium sulfate. After vacuumconcentration, the residue was purified with silica gel column. [FujiSilysia Chemical FL-60D (water content 15%) 7 g, developer: ethylacetate] Yield: 130.6 mg; 98%; pale yellow oil

¹H-NNR spectrum (200 MHz/CD₃OD) of the compound 3

δ: 4.76-4.60 (m, 1H), 4.23-3.65 (m, 6H), 3.65-3.23 (m, 1H), 2.40-1.05(m, 32H), 1.03-0.90 (m, 12H), 0.20-0.03 (m, 6H)

(3) Dess-Martin Oxidization of the Compound 3

Under argon atmosphere, after dissolving 41.5 mg (0.07 mmol) of thecompound 3 in anhydrous dichloromethane 0.56 mL, Dess-Martin reagent118.8 mg (0.28 mmol) was added thereto and agitated for one hour at roomtemperature. Monitoring reaction status with TLC showed that thereaction was not entirely completed. Then Dess-Martin reagent 59.4 mg(0.14 mmol) and anhydrous dichloromethane 0.2 mL were added to thesolution and agitated for 2.5 hours at room temperature. Again,Dess-Martin reagent 59.4 mg (0.14 mmol) and anhydrous dichloromethane0.7 mL were added to the solution and agitated for 2.5 hours at roomtemperature. Additionally, Dess-Martin reagent 89.1 mg (0.21 mmol) andanhydrous dichloromethane 0.7 mL were added to the solution and agitatedfor 13 hours at room temperature. Saturated aqueous sodium thiosulfate20 mL was added to the solution and agitated for three minutes, andthen, the reaction mixture was extracted with ethyl acetate 40 mL twice.Organic layers were combined, washed with saturated sodium bicarbonatesolution 8 mL and saturated saline 8 mL and dried with anhydrousmagnesium sulfate. After vacuum concentration, the residue was purifiedwith silica gel column. [Fuji Silysia Chemical FL-60D (water content15%) 7 g, developer: ethyl acetate/n-hexane=1/2→ethyl acetate]

Yield: 37.9 mg; 92%; pale yellow oil

¹H-NNR spectrum (200 MHz/CDCl₃) of the compound 4

δ: 4.73-4.60 (m, 1H), 4.16 (q, J=7.0 Hz 3/5H), 4.00-3.61 (m, 12/5H),3.61-3.43 (m, 1H), 2.83-2.60 (m, 4/5H), 2.43-1.05 (m, 146/5H), 2.35 (t,J=7.2Hz, 2H), 1.00-0.83 (m, 12H), 0.09 (m, 6H)

(4) Detetrahydropyranylation and de-t-butylmethyl silylation of theCompound 4

After dissolving 37.9 mg (0.064 mmol) of the compound 4 in acetonitrile3.26 mL and cooling it down to 0° C., hydrofluoric acid/acetonitrilemixed solution (3.26 mL, acetonitrile: 46% hydrofluoric acid=10:1) wasadded thereto and agitated for three hours at 0° C. Monitoring reactionstatus with TLC showed that the reaction was not entirely completed.Then the reaction solution was stood still in the refrigerator for 15hours. Even after that, the reaction was not entirely completed. Thenthe reaction solution was agitated for three hours at 10° C.-13° C. andfurther agitated for two hours at 23° C. After neutralizing (pH4) thesolution with saturated sodium bicarbonate solution, saturated saline 1mL was added thereto and then the reaction mixture was extracted withethyl acetate 25 mL three times organic layers were combined, washedwith saturated saline 1 mL and dried with anhydrous magnesium sulfate.After vacuum concentration, the residue was purified with silica gelcolumn to obtain the compound 5. [Fuji Silysia Chemical FL-60D (watercontent 15%) 5 g, developer: ethyl acetate/n-hexane=1/1→3/2→7/3→4/1]

Yield: 4.4 mg; 17.5%; colorless oil

¹H-NNR spectrum (200 MHz/CDCl₃) of the compound 5

δ: 4.25-4.08 (1H, m, 11-H), 3.88-3.64 (1H, m, 15-H), 2.83-2.60 (1H, m,10-H_(β)), 2.35 (2H, t, J=7.2 Hz, 2-H₂), 2.31-2.10 (1H, m, 10-H_(α)),2.10-1.20 (22H, m, 3-H₂, 4-H₂, 5-H₂, 6-H₂, 7-H₂, 8-H, 12-H, 13-H₂,14-H₂, 17-H₂, 18-H₂, 19-H₂), 0.93 (3H, t, J=7.1 Hz, CH₃)

(5) Resolution of Compound 5 into Epimers

64.5 mg of the compound 5 was fractionated by HPLC according to thefollowing condition.

[Fractional Condition]

-   -   Column: Merck Hibar Lichrosorb DIOL (7 μm) 25×250 mm (Lot.        600008)    -   Mobile phase: Hexane/IPA=90/10    -   Elution mode: Isocratic Detection: UV-294 nm    -   Flow rate: 30 mL/min    -   Injection amount: ca. 30 mg(2 mL inj.)/shot.

24 mg of the crude compound 6 (recovery 46%, colorless oil) and 19 mg ofthe crude compound 7 (recovery 36.5%, colorless oil) were obtained.

The crude compound 6 was purified with silica gel column again [FujiSilysia Chemical BW-300 5.2 g, developer: ethylacetate/n-hexane=1/1→3/2→7/3→4/1→5/1]. 19 mg of the purified compound 6(recovery 79%, colorless oil) was obtained.

The crude compound 7 was purified with HPLC again. 15.4 mg of thepurified compound 7 (recovery 81%, colorless oil) was obtained.

¹H-NNR spectrum (200 MHz/CDCl₃) of the compound 6

δ: 4.23-4.09 (1H, m, 11-H), 3.84-3.63 (1H, m, 15-H), 2.73 (1H, dd,J=18.2, 7.0 Hz, 10-H_(β)), 2.35 (2H, t, J=7.2 Hz, 2-H₂), 2.25 (1H, dd,J=18.4, 7.8 Hz, 10-H_(α)), 2.20-1.20 (22H, m, 3-H₂, 4-H₂, 5-H₂, 6-H₂,7-H₂, 8-H, 12-H, 13-H₂, 14-H₂, 17-H₂, 18-H₂, 19-H₂), 0.94 (3H, t, J=7.2Hz, CH₃)

¹H-NNR spectrum (200 MHz/CDCl₃) of the compound 7

δ: 4.25-4.09 (1H, m, 11-H), 3.88-3.65 (1H, m, 15-H), 2.72 (1H, dd,J=18.3, 6.8 Hz, 10-H_(β)), 2.35 (2H, t, J=7.2 Hz, 2-H₂), 2.23 (1H, dd,J=18.5, 7.5 Hz, 10-H_(α)), 2.13-1.20 (22H, m, 3-H₂, 4-H₂, 5-H₂, 6-H₂,7-H₂, 8-H, 12-H, 13-H₂, 14-H₂, 17-H₂, 18-H₂, 19-H₂), 0.93 (3H, t, J=7.1Hz, CH₃)

TEST EXAMPLE (ENTEROPOOLING EFFECT)

Male Wistar rats (Crj Wistar Rat, body weight: 180-200 g) were used.Animals were fasted for 24 hours with free access to water. 5 mL/kg ofdistilled water containing the compound 5, PGE₁ or PGE₂ was orallyadministrated (p.o.), or 2 mL/kg of physiological saline containing thecompound 5 was injected intravenously (i.v.) to the animals. Thirtyminutes after the administration, the animals were euthanized bycervical dislocation, and the abdominal cavity was opened surgically.The intestinal fluid was collected and its volume was measured. The doseof test substance yielding a 50% increase in intestinal fluid volumerelative to the control group, which was received the vehicle only, wasdefined as the ED₅₀ value.

Results are shown in Table 1.

TABLE 1 Test Administration Enteropooling ED₅₀ substance route μg/kgCompound 5 p.o. 0.6 Compound 5 i.v. 0.88 PGE₁ p.o. 420 PGE₂ p.o. 130Compound 5: 13,14-dihydro-15RS-hydroxy-16,16-difluoro-PGE1

The above result indicates that the present compound has a significantenteropooling effect.

1. A compound represented by the formula (IV):

wherein L is oxo and M is hydroxy; A is —COOH; B′ is —CH₂—CH₂—; Z is

wherein one of R₄ and R₅ is hydrogen and the other is hydroxy; R₁ is a—(CH₂)₆— straight chain; X₁′ and X₂′ are halogen atoms; R₂ is a singlebond; and R₃ is lower alkyl.
 2. The compound as described in claim 1,wherein said compound is 13,14-dihydro-16,16-difluoro-prostaglandin E1.3. The compound as described in claim 1, wherein X₁′ and X₂′ arefluorine atoms.